Cutaneous Nerve Fibers Participate in the Progression of Psoriasis by Linking Epidermal Keratinocytes and Immunocytes

Recent studies have illustrated that psoriatic lesions are innervated by dense sensory nerve fibers. Psoriatic plaques appeared to improve after central or peripheral nerve injury. Therefore, the nervous system may play a vital role in psoriasis. We aimed to clarify the expression of nerve fibers in psoriasis and their relationship with immune cells and keratinocytes, and to explore the effect of skin nerve impairment. Our results illustrated that nerve fibers in psoriatic lesions increased and were closely innervated around immune cells and keratinocytes. RNA-seq analysis showed that peripheral sensory nerve-related genes were disrupted in psoriasis. In spinal cord hemi-section mice, sensory impairment improved psoriasiform dermatitis and inhibited the abnormal proliferation of keratinocytes. Botulinum toxin A alleviated psoriasiform dermatitis by inhibiting the secretion of calcitonin gene-related peptide. Collectively, cutaneous nerve fibers participate in the progression of psoriasis by linking epidermal keratinocytes and immunocytes. Neurological intervention may be a new treatment strategy for psoriasis.

Skin Barrier Dysregulation in Psoriasis

The skin barrier is broadly composed of two elements—a physical barrier mostly localised in the epidermis, and an immune barrier localised in both the dermis and epidermis. These two systems interact cooperatively to maintain skin homeostasis and overall human health. However, if dysregulated, several skin diseases may arise. Psoriasis is one of the most prevalent skin diseases associated with disrupted barrier function. It is characterised by the formation of psoriatic lesions, the aberrant differentiation and proliferation of keratinocytes, and excessive inflammation. In this review, we summarize recent discoveries in disease pathogenesis, including the contribution of keratinocytes, immune cells, genetic and environmental factors, and how they advance current and future treatments.

Unconventional Therapy with IgY in a Psoriatic Mouse Model Targeting Gut Microbiome

Psoriasis has a multifactorial pathogenesis and recently it was shown that alterations in the skin and intestinal microbiome are involved in the pathogenesis of psoriasis. Therefore, microbiome restoration becomes a promising preventive/therapy strategy in psoriasis. In our pre-clinical study design using a mice model of induced psoriatic dermatitis (Ps) we have tested the proof-of-concept that IgY raised against pathological human bacteria resistant to antibiotics can alleviate psoriatic lesions and restore deregulated immune cell parameters. Besides clinical evaluation of the mice and histology of the developed psoriatic lesions, cellular immune parameters were monitored. Immune cells populations/subpopulations from peripheral blood and spleen cell suspensions that follow the clinical improvement were assessed using flow cytometry. We have quantified T lymphocytes (CD3ε+) with T-helper (CD4+CD8−) and T-suppressor/cytotoxic (CD8a+CD4−) subsets, B lymphocytes (CD3ε−CD19+) and NK cells (CD3ε−NK1.1+). Improved clinical evolution of the induced Ps along with the restoration of immune cells parameters were obtained when orally IgY was administered. We pin-point that IgY specific compound can be used as a possible pre-biotic-like alternative adjuvant in psoriasis.

A Michael Acceptor Analogue, SKSI-0412, Down-Regulates Inflammation and Proliferation Factors through Suppressing Signal Transducer and Activator of Transcription 3 Signaling in IL-17A-Induced Human Keratinocyte

The activation of signal transducer and activator of transcription 3 (STAT3), as well as up-regulation of cytokines and growth factors to promote STAT3 activation, have been found in the epidermis of psoriatic lesions. Recently, a series of synthetic compounds possessing the Michael acceptor have been reported as STAT3 inhibitors by covalently binding to cysteine of STAT3. We synthesized a Michael acceptor analog, SKSI-0412, and confirmed the binding affinity between STAT3 and SKSI-0412. We hypothesized that the SKSI-0412 can inhibit interleukin (IL)-17A-induced inflammation in keratinocytes. The introduction of IL-17A increased the phosphorylation of STAT3 in keratinocytes, whereas the inactivation of STAT3 by SKSI-0412 reduced IL-17A-induced STAT3 phosphorylation and IκBζ expression. In addition, human β defensin-2 and S100A7, which are regulated by IκBζ, were significantly decreased with SKSI-0412 administration. We also confirmed that SKSI-0412 regulates cell proliferation, which is the major phenotype of psoriasis. Based on these results, we suggest targeting STAT3 with SKSI-0412 as a novel therapeutic strategy to regulate IL-17A-induced psoriatic inflammation in keratinocytes.

Analysis of PPARγ Signaling Activity in Psoriasis

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions triggering the IL17-related signaling cascade. Skin samples of normally looking and lesional skin donated by psoriasis patients and psoriatic CD3+ Tcells samples (n = 23) and samples of healthy CD3+ T cells donated by volunteers (n = 10) were analyzed by real-time PCR, ELISA and immunohistochemistry analysis. We found that the expression of PPARγ is downregulated in human psoriatic skin and laser treatment restores the expression. The expression of IL17, STAT3, FOXP3, and RORC in psoriatic skin before and after laser treatment were correlated with PPARγ expression according to the reconstructed model of PPARγ pathway in psoriasis.In conclusion, we report that PPARγ weakens the expression of genes that contribute in the development of psoriatic lesion. Our data show that transcriptional regulation of PPARγ expression by FOSL1 and by STAT3/FOSL1 feedback loop may be central in the psoriatic skin and T-cells.

Del-1 in psoriasis induced the expression of αvβ3 and α5β1 in endothelial cells

Objective: Psoriasis is a chronic inflammatory skin disease highly depending on angiogenesis. Our prior results showed that the mRNA and protein of Del-1 in dermal mesenchymal stem cells (dMSCs) was up-regulated from psoriasis. Our aim was further to investigate the role of Del-1 from dMSCs in the pathogenesis of psoriasis and confirm the effect of Del-1 on the pathogenesis of psoriasis. Methods: We conducted an immunohistochemistry experiment to further investigate the expression of Del-1in psoriatic lesions. In addition, dMSCs with over-expressed Del-1 via the lentiviral vector of Del-1 were co-cultured with ECs, and the protein expression of integrins (αvβ3, αvβ5 ,and α5β1) of ECs were detected by western blotting. Results: This research showed that Del-1 was significantly increased in lesions of patients with psoriasis (p< .05, 9.96 vs. 2.18), and Del-1 from dMSCs successfully induced up-regulation of integrins α5β1 and αvβ3 (all p < .05). Conclusion: This study demonstrated that Del-1 from dMSCs was involved in the pathogenesis of psoriasis through induced angiogenesis. And Del-1, αvβ3 and α5β1 may be potential new targets for inhibiting angiogenesis in psoriasis.

Remission of Recalcitrant Psoriasis on Combined Biologic Therapy With Infliximab and Ustekinumab

Introduction: Anti-TNF treatment is effective for inflammatory bowel disease (IBD), however it also has the potential to cause paradoxical psoriasis which can be challenging to manage. Discontinuation of anti-TNF agents may improve psoriatic lesions but may worsen IBD. Combining biologic therapies, though not yet commonly practiced, may be a useful approach to the treatment of both conditions. Case Presentation: We describe a case of paradoxical palmoplantar psoriasis in a 48-year-old woman with ulcerative colitis (UC). Her UC was well-managed on infliximab. Following trials of several other topical and systemic therapies for her psoriatic lesions, she ultimately received relief on combined ustekinumab and infliximab therapy without flare of her IBD. Discussion: While other publications report success using ustekinumab for paradoxical psoriasis following cessation of infliximab, this case report highlights successful treatment using a combination of ustekinumab and infliximab with no reported adverse effects at 3 months. Conclusion: Discontinuation of the anti-TNF agent and use of a single biologic that may treat both IBD and psoriasis is a treatment option. Additionally, combining biologic therapies, though not yet commonly practiced, may be a useful, albeit costly, approach to prevent potential flares of IBD that may accompany cessation of some biologics. Further studies may be beneficial to assess for long term adverse effects.